Prevalence of allergic disease continues to rise worldwide. An estimated 40% of the population is sensitized, i.e. have IgE antibodies to foreign proteins in the environment. More worrisome, 40%-50% of school-going children worldwide are getting sensitized to one or more allergens. For example, about 6 million children in the United States suffer from food allergies against peanut, milk, egg, shellfish etc. Other forms of sensitizing allergens can include a multitude of foreign proteins derived from pollens, insects, dust mites, and vegetation, which can manifest as different diseases including allergic rhinitis (hay fever), sinusitis, asthma, and skin reactions. One might even consider allergy as the emerging epidemic of the industrialized world. 'Allergen- specific immunotherapy (ASI)' is the only disease-modifying treatment available, which can desensitize humans to their allergen. Subcutaneous immunotherapy (SCIT) has been the standard for performing ASI, and it involves repeated subcutaneous injection of the allergen to reorient the abnormal cellular and humoral immune responses. SCIT has several drawbacks, including the need for repeated allergen injections over multiple years, the need to be in a clinic to receive the treatment, and a risk of life-threatening systemic anaphylactic reaction. The goal of this proposed research is to develop a novel minimally-invasive cutaneous immunotherapy (CIT) using allergen-coated microneedles (MNs). MNs comprise of microscopic projections on a patch that can be self-applied on the skin, and could take the fear, pain, and inconvenience out of allergy immunotherapy. Our preliminary data presented in this proposal shows that MN-CIT is at least as effective as SCIT. Our specific aims are: (i) Develop monoallergen-coated MNs and evaluate their short and long term therapeutic effectiveness relative to SCIT, (ii) Develop microneedles for multiallergen immunotherapy and establish their efficacy relative to SCIT, and (iii) Characterize mechanism of MN-CIT and establish that MN-CIT is allergen-specific. If successful these studies will provide data necessary to support further development of microneedles for painless allergy immunotherapy.